Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
  • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
  • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
  • A61K9/2846—Poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

• the invention relates to a multilayer pharmaceutical form with a neutral methacrylate copolymer as a binder for the active ingredient.
• neutral methacrylate copolymers that is to say methacrylate copolymers, which predominantly consist of (at least 95%) (meth) acrylate monomers with neutral residues, such as methyl methacrylate or ethyl acrylate, as coating and binders for pharmaceutical forms Delayed drug release has been known for a long time.
• WO 01/68767 describes a dispersion, suitable for use as a coating and binder for pharmaceutical forms, with a solids content of 10-70% by weight consisting of
• WO 01/68767 also mentions that layers of multi-layer coating systems can be produced.
• a core containing, for example, basic or water-sensitive active ingredients, with an insulating layer of another coating material such as cellulose ethers, Celluloseester, cationic polymethacrylates (such as EUDRAGIT ® E I00, -RL 100 - RS 100, Rohm GmbH) are provided, before the coating agent according to the invention is applied.
• further coatings can then be applied, for example with an odor or taste-masking effect or with an appealing coloring or gloss effect.
• a typical methacrylate copolymer according to WO 01/68767 can e.g. B. from 25 - 35 wt .-% methyl methacrylate and 75 to 65 wt .-% ethyl acrylate. If necessary, small amounts of comonomer from other vinyl monomers may also be present.
• Multilayer dosage forms are well known.
• WO 01/68058 describes e.g. B. the use of a multilayer pharmaceutical form, which is essentially built up
• a copolymer or a mixture of copolymers which is composed of 85 to 98% by weight of radically polymerized C1- to C4-alkyl esters of acrylic or methacrylic acid and 15 to 2 wt .-% (meth) acrylate monomers with a quaternary ammonium group in the alkyl group and one
• the present invention is based on WO 01/68767.
• the multilayered pharmaceutical form described therein allows the setting of variable release profiles and a precise and reproducible release of active substance under defined conditions.
• Another problem is an active ingredient release characteristic that is apparently influenced by the ionic strength of the surrounding medium.
• Oral dosage forms are often ingested with water and the ionic strength in the stomach and intestines, e.g. B. are subject to certain fluctuations due to food intake, the dosage forms are exposed to changing ionic strengths in vivo. In vivo, this can lead to not always reproducible drug release characteristics. Drug forms are therefore desirable whose active ingredient release characteristics remain largely unaffected by the ionic strength of the surrounding medium.
• the inner coating layer usually has to be formulated with the aid of plasticizers in order to ensure sufficient flexibility of the films.
• release agents such. B. talc or glycerol monostearate is usually essential to prevent the coated units from sticking together during or after the application of the inner coating layer.
• multilayered dosage form made up of
• the inner coating consists essentially of a methacrylate copolymer which is composed of at least 90% by weight of (meth) acrylate monomers with neutral residues, has a minimum film-forming temperature in accordance with DIN 53 787 of at most 30 ° C. and the pharmaceutical active ingredient in contains bound form.
• the dosage form according to the invention is easier to produce, since the active ingredient can be applied in one step with the inner polymer coating.
• a methacrylate copolymer which is composed of at least 90% by weight of (meth) acrylate monomers with neutral residues has a minimum film-forming temperature in accordance with DIN 53 787 of at most 30 ° C. makes it possible to largely or even completely do without additives such as plasticizers or release agents.
• a similarly retarding release of the active substance bound in the polymer is obtained, as is the case in WO 01/68767 with an active substance bound in the core and a coating of (meth) acrylate copolymers with quaternary amino groups is possible.
• An important advantage of the pharmaceutical form according to the invention is that the release of active substance at a constant pH in a hypotonic and an isotonic medium is almost not influenced by the ionic strength.
• the invention relates to a
• Multilayer pharmaceutical form which contains a pharmaceutical active ingredient in the release test according to USP for two hours at pH 1, 2 and subsequent buffering to a pH of at least 6.8 less than 5% of the active ingredient in the period up to 2.0 hours after the start of the test and at the time releases 30 to at least 80% eight hours after the start of the test
• the inner coating consists essentially of a methacrylate copolymer which is composed of at least 90% by weight of (meth) acrylate monomers with neutral residues, has a minimum film-forming temperature in accordance with DIN 53 787 of at most 30 ° C. and the pharmaceutical active ingredient in contains bound form.
• Carriers or neutral cores for the coatings are tablets, granules, pellets, crystals of regular or irregular shape.
• the size of granules, pellets or crystals is usually between 0.01 and 2.5 mm, that of tablets between 2.5 and 30.0 mm.
• the cores can contain other pharmaceutical auxiliaries: binders, such as lactose, cellulose and their derivatives, polyvinylpyrrolidone (PVP), humectants, disintegrants, lubricants, disintegrants, starch and their derivatives, sugar solubilizers or others.
• binders such as lactose, cellulose and their derivatives, polyvinylpyrrolidone (PVP), humectants, disintegrants, lubricants, disintegrants, starch and their derivatives, sugar solubilizers or others.
• the inner coating b) essentially consists of a methacrylate copolymer which consists of at least 90% by weight of (meth) acrylate monomers with neutral residues and a minimum film-forming temperature according to DIN 53 787 of at most 30 ° C, particularly preferably at most 25 ° C, with an active pharmaceutical ingredient bound therein.
• the layer thickness of the inner coating can preferably be between 10 and 300 ⁇ m
• the methacrylate copolymer for the inner coating b) consists of at least 90, in particular 95, preferably 97, in particular 99, particularly preferably 100% by weight of (meth) acrylate monomers with neutral residues, in particular C to C 4 alkyl residues.
• Suitable monomers are e.g. B. methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate. Methyl methacrylate, ethyl acrylate and methyl acrylate are preferred.
• the polymers which are neutral per se, can contain small amounts of methacrylic acid or acrylic acid, which practically do not change the water-insolubility of the polymer, but can influence the swelling and allow pH-dependent control of the permeability.
• vinylically polymerizable monomers in particular (meth) acrylate monomers with polar or ionic radicals, e.g. As methacrylic acid or acrylic acid may be included.
• the (meth) acrylate copolymer has a minimum film-forming temperature according to DIN 53 787 of at most 30 ° C
• the methacrylate copolymer can preferably have a glass transition temperature Tg of -25 ° C to + 20 ° C, preferably -10 ° C to 0 ° C, determined by the DSC method (ISO 11357).
• the methacrylate copolymer of the inner coating may e.g. B. from 25-35% by weight of methyl methacrylate, 75 to 65% by weight of ethyl acrylate and not more than 1% by weight of methacrylic acid, the proportions adding up to 100% by weight.
• the (meth) acrylate copolymer for the inner coating b) can be present and processed as an organic solution or as a dispersion.
• the (meth) acrylate copolymer for the inner coating b) is preferably used in the form of a dispersion with a solids content of 10-70% by weight.
• the corresponding dispersion particularly preferably contains 1 to 10, preferably 2 to 8, particularly preferably 4 to 6% by weight, based on the solids content of a nonionic emulsifier with an HLB value of 15.7 to 19.5. Is suitable for.
• Emulsifiers control the course of the emulsion polymerization process by allowing the chain-building reaction of the emulsified monomers in the water phase. They are therefore an auxiliary necessary for the production and determining the properties of the dispersion. They cannot usually be replaced without fundamentally changing the relevant properties of the dispersion.
• the HLB value is a measure of the hydrophilicity or lipophilicity of nonionic surfactants introduced by Griffin in 1950. It can be determined experimentally using the Marszall phenol titration method; see. "Perfumery, Cosmetics", Volume 60, 1979, pp. 444-448; further references in Römpp, Chemie-Lexikon, ⁇ . Aufl. 1983, p.1750. See also z. B. U.S. 4,795,643 (Seth)).
• HLB value hydrophilic / lipophilic balance
• the HLB values of the emulsifiers have a significant influence on the crystallization of the emulsifier. Ideally, these values are between 15, 7 and 16.2. After drying, the emulsifiers crystallize above the claimed range. Emulsifiers with an HLB value below the claimed range cannot stabilize the dispersion sufficiently, which can be recognized from the strong coagulum formation.
• the HLB values were either taken from the literature (Fiedler: Lexicon of auxiliary substances) or according to WC Griffin (special print from perfumery and cosmetics 64, 311-314, 316 (1983); Weghig Verlag, Heidelberg / Pharmind Ind. 60 No. 1 ( 1998); dielectric thermal analysis).
• the emulsifier should be toxicologically safe and therefore preferably non-ionic emulsifiers.
• Suitable emulsifier classes are ethoxylated fatty acid esters or ethers, ethoxylated sorbitan ethers, ethoxylated alkylphenols, glycerol or sugar esters or wax derivatives
• Suitable emulsifiers are, for example, polyoxyethylene glycerol monolaurate, polyoxyethylene glycerol monostearate, polyoxyethylene-20-cetyl stearate, polyoxyethylene-25-cetyl stearate, polyoxyethylene (25) oxypropylene monostearate, polyoxyethylene-20-sorbitan monopalmitate, polyoxyethylene-16-tert.oylylphenol monocetyl ether, ethoxylated castor oil, polyoxyethylene sorbitol wool wax derivatives, polyoxyethylene (25) propylene glycol stearate and polyoxyethylene sorbitol ester
• Polyoxyethylene 25 cetyl stearate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 16 tert.octylphenol and polyoxyethylene 20 cetyl ether are preferred.
• a dispersion is obtained in a manner known per se by aqueous emulsion polymerization in a batch or feed process, semi-continuously or continuously (see, for example, DE 195 03 099 A1).
• the radical polymerization of the monomers in the presence of the emulsifier takes place by means of radical-forming water-soluble polymerization initiators, in which the radical formation can take place thermally or via redox processes. If necessary, molecular weight regulators are added to adjust the molecular weights.
• Emulsion polymers are usually produced in concentrations between 10 and 70% by weight. A solids content of 30-50% by weight is favorable. Batch production is usually carried out in stirred tank reactors.
• Antifoam emulsion and stabilizers can be added to the dispersion.
• the active ingredient is preferably bound by aqueous spraying of an active ingredient-containing (meth) acrylate copolymer dispersion onto the cores a), for. B. sucrose pellets, binding the active ingredient after evaporation or volatilization of the water.
• the product temperature during the spray application can, for. B. 20 to 40, preferably 25 to 35 ° C.
• a variant of the process is the so-called powder layering process, in which the (meth) acrylate copolymer dispersion is sprayed and the active ingredient is added in powder form.
• the processing of the active ingredient can preferably by stirring in water with initially vigorous mixing, for. B. by 5 to 15 minutes of mixing z. B. with a high-speed mixer (homogenizer).
• the suspension or solution thus obtained can then be added to the (meth) acrylate copolymer dispersion.
• the mixture should expediently and preferably also be stirred continuously during the spraying process.
• a water-soluble active ingredient can be added to the polymer dispersion in dissolved form and then sprayed on.
• the active ingredient is present in the copolymer of the inner coating b) either in crystalline form (solid dispersion) or in dissolved form (solid solution).
• the active ingredient / polymer ratio of the inner layer can be 20 to 1 to 1 to 20, preferably 1 to 1 to 1 to 3.
• the pharmaceutical form according to the invention is suitable for the administration of basically any pharmaceutical active ingredients which should preferably be released in the small intestine and / or colon, and in particular those which can advantageously be administered in a delayed form, such as antidiabetic agents, Analgesics, anti-inflammatory drugs, anti-inflammatory drugs, anti-hypotensive agents, anti-hypertensive agents, psychotropic drugs, tranquilizers, anti-emetic agents, muscle relaxants, glucocorticoids, agents for the treatment of colitis uicerosa or Crohn's disease, anti-allergic agents, antibiotics, anti-epileptics, anti-coagulant drugs, anti-coagulant drugs, anti-coagulant drugs, anti-coagulant drugs, anti-coagulant drugs, anti-coagulant drugs, anti-coagulant drugs, anti-coagulant drugs, anti-coagulant drugs, anti-coagulant drugs, anti-inflammatory drugs Gout agents, hormones and their inhibitors, cardiac glycosides, immunotherapeutics and cytokines, laxative
• Suitable active ingredients are acarbose, beta-blockers, non-steroidal anti-inflammatory drugs, cardiac glycosides, acetylsalicylic acid, virustatic agents, aclarubicin, acyclovir, cisplatin, actinomycin, alpha and beta sympatomimetics, (Dmeprazole, allopurinol, metalodrexinol aminodrexinol, alproodinolate, alproodinolate, alproodinolate -Aminosalicylic acid, amitriptyline, amoxicillin, anastrozole, atenolol, azathioprine, balsalazide, beclomethasone, betahistine, bezafibrate, bicalutamide, diazepam and diazepam derivatives, budesonide, bufexamac, buprenorphal, cadzezalapin, cadzezalamapin, ca
• agents for treating colitis uicerosa or Crohn's disease such as salicylates, for example 5-aminosalicylic acid, 4-aminosalicylic acid, olsalazine, balsalazine, sulfasalazine, corticosteroids, such as budesonide, prednisolone, methylprednisolone, prednisone, dexamethasone, anti-chloronate, hydrocinolonic acid, and hydrocinolonic acid
• analgesics such as tramadol, morphine, codeine,
• proton pump inhibitors such as omeprazole
• virus statics such as amantadine, memantadine, ribavirin and acyclovir
• lipid-lowering agents such as simvastatin or pravastatin
• H2-blockers such as ranitidine or antibiotics such as macrolides:
• the active compounds can also be used in the form of their pharmaceutically acceptable salts or derivatives, and in the case of chiral active compounds both optically active isomers and racemates or mixtures of diastereoisomers can be used.
• the compositions according to the invention can also contain two or more active pharmaceutical ingredients.
• the outer coating c) consists essentially of (meth) acrylate copolymers which consist of 40 to 95% by weight of radically polymerized units of C to C 4 alkyl esters of acrylic or methacrylic acid and 5 to 60% by weight of ( Meth) acrylate monomers with an anionic group in the alkyl group.
• the proportions mentioned add up to 100% by weight.
• methyl methacrylate, butyl methacrylate, butyl acrylate or hydroxyethyl methacrylate may be included.
• C to C 4 alkyl esters of acrylic or methacrylic acid are in particular methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate.
• a (meth) acrylate monomer with an anionic group in the alkyl group can e.g. As acrylic acid, but preferably methacrylic acid.
• the carboxyl groups can be up to 30 mol%, preferably up to 5 to 15 mol%, partially neutralized.
• Anionic (meth) acrylate copolymers of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of methyl methacrylate or 60 to 40% by weight of ethyl acrylate are suitable.
• Anionic (meth) acrylate copolymers of 20 to 40% by weight methacrylic acid and 80 to 60% by weight methyl methacrylate are also suitable.
• anionic (meth) acrylate copolymers of 20 to 34% by weight of methacrylic acid and / or acrylic acid, 20 to 69% by weight of methyl acrylate, 0 to 40% by weight of ethyl acrylate and optionally 0 to 10% by weight of others vinyl copolymerizable monomers, with the proviso that the glass transition temperature of the copolymer according to ISO 11357-2, point 3.3.3, is at most 60 ° C. (Type EUDRAGIT® with medium content of methacrylic acid).
• the copolymer is composed in particular of radical-polymerized units of
• the pharmaceutical form according to the invention with the outer coatings mentioned, in particular the type consisting of 10 to 30% by weight, methyl methacrylate, 50 to 70% by weight methyl acrylate and 5 to 15% by weight methacrylic acid is suitable especially for dosage forms that release the active ingredient in the distal lleum or colon.
• the pharmaceutical form according to the invention with the outer coatings mentioned, in particular the type consisting of 10 to 30% by weight, methyl methacrylate, 50 to 70% by weight methyl acrylate and 5 to 15% by weight methacrylic acid is suitable especially for dosage forms that contain the following classes of active substances and active substances and can be used to treat Crohn's disease or Uicerosa colitis.
• the classes of active ingredients of aminosalicylates, sulfonamides or glucocorticoids should be mentioned.
• Particularly preferred active ingredients are 5-aminosalicylic acid, olsalazine, sulfalazine, prednisone, prednisolone or budesonide.
• the pharmaceutical form is particularly suitable for immunomodulatory active substances from the classes of proteins, peptides, oligonucleotides with a suspected active site on the intestinal mucosa and especially on the "payer 's plaques" in the colon mucosa.
• the pharmaceutical form according to the invention with the outer coatings mentioned, in particular the type consisting of 10 to 30% by weight, methyl methacrylate, 50 to 70% by weight methyl acrylate and 5 to 15% by weight methacrylic acid are suitable especially for dosage forms, the following Active substance classes and active substances included.
• the active substance classes are enzymes, a peptide hormone, immunomodulatory proteins, antigens, antibodies or oligonucleotides.
• active ingredients are pancreatin, insulin, human growth hormone (hGH), corbaplatin, intron A, calcitonin, cromalyn, interferons, calcitonin, granulocyte colony stimulating factor (G-CSF), interleukin, parathyroid hormones, glucagon, pro-somatostatin, somatostatin, Detirelix, Cetrorelix, vasopressin, 1 -deaminocysteine-8-D-arginine-vasopressin, leuprolide acetate or an antigen derived from grasses or other plants such as e.g. B. rye, wheat, barley, oats, Bermuda grass, horsetail, maple, elm, oak, plane tree, poplar, cedar, horsetail, thistles.
• grasses or other plants such as e.g. B. rye, wheat, barley, oats, Bermuda grass, horsetail, maple, elm, oak, plane tree,
• the (meth) acrylate copolymer of the outer coating c) preferably consists essentially or exclusively of the monomers methacrylic acid, acrylic acid, methyl methacrylate, methyl acrylate and / or ethyl acrylate in the proportions given above.
• the proportions mentioned add up to 100% by weight.
• small amounts in the range from 0 to 10, e.g. B. 1 to 5 wt .-% of other vinyl copolymerizable monomers, such as. B. butyl methacrylate, butyl acrylate or hydroxyethyl methacrylate may be included.
• copolymers mentioned can be obtained in a manner known per se by radical substance, solution, bead or emulsion polymerization. Before processing, they must be brought into the particle size range according to the invention by suitable grinding, drying or spraying processes. This can be done by simply breaking extruded and cooled granulate strands or by hot cutting.
• the (meth) acrylate copolymer for the outer coating c) can be present and processed as an organic solution or as a dispersion.
• the (meth) acrylate copolymer for the inner coating b) is preferably used in the form of a dispersion with a solids content of 10-70% by weight.
• the (meth) acrylate copolymer c) is preferably in the form of a dispersion, for. B. with a water content of 60 to 80 wt .-% before.
• the carboxyl groups can contain up to 30 mol%, preferably 5 to 15 mol%, of a base, e.g. B. NaOH, be partially neutralized.
• the inner layer b) is preferably produced by aqueous spraying of an active ingredient-containing (meth) acrylate copolymer dispersion onto cores, e.g. B. sucrose pellets, binding the active ingredient after evaporation or volatilization of the water.
• the product temperature during the spray application can, for. B. 20 to 40, preferably 25 to 35 ° C.
• the active ingredient-containing (meth) acrylate copolymer dispersion it is not necessary for the active ingredient-containing (meth) acrylate copolymer dispersion to have a release agent, for. B. talc, and a plasticizer, such as triethyl citrate.
• the processing of the active ingredient can preferably by stirring in water with initially vigorous mixing, for. B. by 5 to 15 minutes of mixing z. B.
• the suspension thus obtained can then be added to the (meth) acrylate copolymer dispersion.
• the mixture should expediently and preferably also be stirred continuously during the spraying process.
• the layer thickness of the inner coating can preferably be 10-300 ⁇ m.
• Release agents have the following properties: They have large specific surfaces, are chemically inert, are easy to pour and have fine particles. Because of these properties, they can advantageously be distributed homogeneously in melts and reduce the stickiness of polymers which contain highly polar comonomers as functional groups.
• drying agents are:
• Barium sulfate, carbon black and cellulose Barium sulfate, carbon black and cellulose.
• release agents are:
• GMS glycerol monostearate
• stearyl alcohol glycerol behenic acid esters
• cetyl alcohol palmitic acid
• cannula wax cannula wax
• the inner layer b) contains no more than 1% by weight, preferably no release agent. If a release agent is used, glycerol monostearate is preferred.
• Plasticizers generally have a molecular weight between 100 and 20,000 and contain one or more hydrophilic groups in the molecule, e.g. B. hydroxyl, ester or amino groups. Citrates, phthalates, sebacates, castor oil are suitable. Examples of suitable ones Plasticizers are alkyl citrate, propylene glycol, glycerol ester, alkyl phthalate, alkyl sebacate, sucrose ester, sorbitan ester, diethyl sebacate, dibutyl sebacate and polyethylene glycols 4,000 to 20,000.
• Preferred plasticizers are tributyl citrate, triethyl citrate (TEC), acetyl triethyl citrate, dibutyl sebacate and diethyl sebacate.
• the amounts used in the outer layer c) can be between 0 and 35, preferably 2 to 10,% by weight, based on the (meth) acrylate copolymer.
• the inner layer b) generally contains at most 20% by weight, preferably no longer 12% by weight and particularly preferably no plasticizer.
• auxiliaries B to name stabilizers, dyes, antioxidants, wetting agents, pigments, glossing agents etc. They primarily serve as processing aids and are intended to ensure a safe and reproducible manufacturing process and good long-term storage stability. Further pharmaceutically customary auxiliaries can be present in amounts of 0.001% by weight to 30% by weight, preferably 0.1 to 10% by weight, based on the copolymer.
• the multilayered pharmaceutical form according to the invention has in particular the property that the percentage active ingredient release values in a hypotonic and an isotonic release medium, based on phosphate buffer pH 6.8, at no time by more than 10%, preferably not, in the period from 1 to 5 hours deviate from each other by more than 5%.
• Phosphate buffer pH 6.8 with an osmotic concentration of 80 osmol can be used as the hypotonic medium.
• Phosphate buffer pH 6.8 can be used as an isotonic medium, in which an osmotic concentration of 300 osmol is set by adding NaCl.
• the multilayered pharmaceutical form can furthermore be characterized in that it contains less than 5% of the active ingredient in the release test according to USP for two hours at pH 1, 2 and subsequent buffering to pH 7.0 in the period up to 2.0 hours after the start of the test Releases 30 to 100% eight hours after the start of the test.
• Example 1-3 Description of the experiment for spray embedding of budesonide in EUDRAGIT ® NE 30 D (copolymer of 65% by weight ethyl acrylate and 35% by weight methyl methacrylate)
• Example 1 EUDRAGIT ® NE 30 D: budesonide 2.5: 1
• Example 2 EUDRAGIT ® NE 30 D: budesonide 1: 6: 1
• a sample was taken at 1% and 2% polymer application. All batches were mixed with 0.5% Aerosil 200 after manufacture to prevent the pellets from sticking during storage.
• the active ingredient budesonide probably has the effect of a release agent.
• the separating effect of budesonide was checked by completely dispensing with the use of talc as a separating agent in Example 3 (EUDRAGIT ® NE 30 D: Budesonide 1, 6: 1).
• Solids content dispersion (m / m) 10.5% 12.0% 9.0%
• Fig. 1 shows the comparative release profiles of example 1 (EUDRAGIT ® NE 30 D: budesonide 2.5: 1) and example 2 (EUDRAGIT ® NE 30 D: budesonide 1: 6: 1) in phosphate buffer pH 6.8.
• the release rate decreases as the amount of polymer applied increases, which means that the film thickness increases.
• the approval for the 1% polymer orders is quantitative within 3-4 hours. With a larger LTS order, a lowering of the release rate can be observed.
• Example 1 3% polymer coatings of Example 1 (Eudragit NE 30 D: Budesonide 2.5: 1) were tested for their robustness with regard to the osmotic concentration of the release medium.
• This osmolarity range covers the preprandial conditions in the proximal GI tract with and without simultaneous intake of the pellets with up to 250 ml of water. It can be observed that the osmolarity has no influence on the release from the pellets.
• the release is very robust (Fig. 2).
• Fig. 2 Release profiles of Example 1 with 3% (m / m) polymer application in phosphate buffer and an isotonic and hypotonic osmolarity.
• Example 4 Modification of the start of the release by film coating with Eudragit® FS 30 D.
• the coating batch corresponds to example 1 (spray embedding of budesonide in Eudragit NE 30 D, polymer: active ingredient ratio 2.5: 1, 3% m / m LTS) was coated with Eudragit FS 30 D to modify the start of the release.
• the resulting batch (2-24) was examined in more detail with regard to its in vitro release behavior. The goal was to slow the release of budesonide, with the release only beginning in the terminal small intestine.
• the release studies carried out in pharmacopoeia buffers with pH 1, 2; 6.8; 7.2 and 7.5 show for test 4 with 20% (m / m) LTS of Eudragit® FS 30 D that the release at pH 1, 2 and 6.8 is prevented.
• Example 5 Enteric coating with Eudragit® L 30 D-55
• Experiment 5 was selected as a prototype for the therapy of Crohn's disease and was characterized more precisely by in vitro release studies.
• the batch consists of a spray embedding of budesonide in Eudragit® NE 30 D with 1% (m / m) LTS application and an enteric coating polymer, namely Eudragit® L 30 D-55 with 10% or 20% LTS application. Since the enteric polymer coating is in direct contact with the embedding matrix, it was of interest to investigate the possible influence of the coating on the release from the embedding.
• the test for gastric juice resistance was carried out according to the monograph of USP 24 "Delayed-release (Enteric-coated) Articles - General Drug Release Standard", Method A.
• Figure 5 Release profiles of experiment 5 in dissolution media (phosphate buffer, Ph 6.8) with different osmolarity. Embedding in Eudragit® NE 30 D (experiment 3) and coating with Eudragit® L 30 D (copolymer of 50% by weight methyl methacrylate and 50% by weight methacrylic acid)
• Example 6 (not according to the invention, compared to example 1) formulation compared to Example 1) with Eudragit RL 30D as retarding coating and EUDRAGIT ® L 30 D-55 as the enteric film coating (MR). Weights in grams.
• Lacquer dry substance (LTS) [g] 60 50
• Solids content dispersion (m / m) 20.4% 20%

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